Its preparation



3,132,146 ANALOG F ltl-METI-IOXY DESERPDINE ITS PREPARATlON Andre Allaisand Pierre Girault, Paris, France, assignors, by mesne assignments, toRoussel-Uclaf, S.A., Paris, France, a corporation of France N0 Drawing.Filed Oct. 18, '1961, Ser. No. 146,013 1 Claims priority, applicationFrance Oct. 26, 1960 4 Claims. (Cl. 260 -287) This invention relates toa new derivative of yohimbane, its process of preparation and theintermediates produced. Particularly, this invention relates to theracemic and optically active 18 3-(3',4',5'-trimethoxybenzoyloxy)-10,17tx-dirnethoxy 16B carbo-carboxymethoxy-Zv5,200- yohirnbane of theformula:

and its therapeutically-acceptable basic addition salts.

There have already been described a large number of esters of reserpineand its analogs, obtained either by changing the acid radical of thetrimethoxy-benzoic acid in the 18 position, by making variationsin thealkyl radical which esterifies the carboxyl group in the 16 position, orby making various substitutions to the pentacyclic yohimbane structure.However, esters of the reserpic acid series in which the 16 positioncarries a free acid function are not known. 7 An object of thisinvention is the obtention of 18 8- (3',4,5' trimethoxybenzoyloxy)10,1704 dimethoxy- 165 carbo carboxyrnethoxy 35,20 yohimbane of theformula:

and particularly the levorotatory isomer either as a free acid or as asalt with a therapeutically-acceptable base.

United States Patent C) 3,132,146 Patented May 5, 1964 The levorotatoryhydrochloride of 18 8-(3',4',5-trimethoXybenz0yloxy)-10,17a-dimethoxy16p carbobenzyloxy-3fl,20oc-yohirnbane;

Levorotatory 1 8/8-(3,4,5 -trimethoxybenzoyloxy) -10,

. h-dimethoxy-l 6fl-carboXy-318,20a-yohimbane (free ase);

The levorotatory hydrochloride of 18;8-(3,4',5'-trimethoxybenzoyloxy)-10, 17 a-dimethoxy-16B-carboxy-3B, 20a-yohimbane;

Levorotatory 18 B- 3,4',5 -trin1ethoxybenzoyloxy) 1 0,

17a-dimethoXy-16fi-carbochloride-3 3-2Ou-yohimbane.

These and other objects of the invention will become more apparent asthe description thereof proceeds.

We have discovered, and this is our invention, an analog of reserpine,namely, lO-rnethoxy deserpidine, whose carboxyl group in the 16 positionis esterified by glycolic acid,

such that the resulting product carries a free carboxyl group. The newcompound according to the invention, 18B (3',4',5' trimethoxybenzoyloxy)10,170; dimethoxy-lfi-carbocarboxymethoxy 36,205: yohimbane orcarboxyrnethyl IO-methoxydeserpidate has the Formula I:

. A further object of the invention is the development of i Incomparison with known compounds of the series of reserpine and itsanalogs,'the product of the invention can be easily solubilized in waterin the form of a salt of an appropriate therapeutically-acceptableinorganic or organic base. The product has pronounced anti-hypertensiveproperties and it is devoid of a neurodepressor effect,

duced by theprocess illustrated in' the flow diagram of.

Table I.

TABLE I w "(up onto .Hot \N N ti H H I H/@ V (|)CH3 o o H C a )CHs (IV)t .HCI N N {TH/{1P1 H (|)CH3 no-t z \O(]O on;

o 60H 0 i 3 OCHS (v CH30\ V an IE V OOH:

o born 0 CH O a born (I) This process utilizes as starting material the16,18-1achimbane, II, by the following reactions:

I pound III by an esterification derivative of 3,4,5-trimeth- (a)Esterification with benzyl alcohol in the presence of an alkali metalbenzylate of the lactone II to give 185- hydroxy-lO,l7a-dimethoxy-16Bcarbobenzyloxy 35,200;- yohimbane, III; p

(b) Esterfication of the 18-hydroxyl group of Comoxy benzoic acid, suchas the anhydride or chloride, in the presence of an organic nitrogensolvent, which furnishes l8,8-(3',4',5'- imethoxybenzoyloxy)-10,l7oz-dimethoxy-l6B-carbobenzyloxy-3fi,20ot-yohimbane, IV;

V (c) Hydrogenolysis of compound IV to remove benzyl alcohol and to give18,8-(3',4,5'-trimethoxybenzoyloxy)-10,l7ot-dimethoxy-16,8-carboxy-3p,20 a-yohimbane, V;

(d) Esterification with glycolic acid of the carboxyl in the 16 positionof 18B-(3,4',5'-trimethoxybenzoyloxy)- l0,17a-dimethoxy-l6 3-carboxy3B,20ot yohimbane, V. Advantageously, this esterification isaccomplished by previously transforming18p-(3',4,5-trimethoxybenzoyloxy)-10,l7a-dimethoxy-l6fl-carboxy3,8,20a-yohimbane, V, into the corresponding acid chloride, VI. I

In the preferable mode of execution of the abov process:

(a) The esterification of the lactone with benzyl alcohol is effectedunder anhydrous conditions with benzyl alcohol in the presence of sodiumbenzylate. The reaction is conducted in the presence of an inert organicsolvent such as methylene chloride at reflux temperatures.

(b) The esterification of the l8-hydroxyl group is effected with3,4,5-trimethoxybenzoic acid anhydride in the presence of pyridine andtriethylamine at a temperature between about C. and about C r I (c) Thehydrogenolysis to remove benzyl alcohol is eifected with hydrogen in thepresence of a hydrogenolysis catalyst such as palladized carbon black inan inert organic solvent such as methanol.

' (d) The esterification of the 16-carboxyl with glycolic acid iseffected by reacting the hydrochloride saltof compound V in an inertorganic solvent such as chloroform with phosphorous pentachloride togive the corresponding acid chloride VI. The solution in chloroform ofthe acid chloride is reacted with glycolic acid in the presence of anorganic nitrogen solvent such as pyridine and the desired compound I isisolated.

The following example is given as purely illustrative without limitingthe invention in any manner. It will be obvious to one skilled in theart that other procedures may be employed to practice the invention.

EXAMPLE Preparation of Levorotatory 18p-(3,4,5'-Trimthoxybenzoyloxy)-l0,17a-Dimethyl-16,B CarboCarboxymethoxy-3fi,20a.-Y0himbane, I

STEP A.-IPREPARATION OF LEVOROTATOR'Y ISM-HY- DROX Y -10,17DIMETHOXY1613 CARBOBENZYLOXY- 3,3,20a-YOHIMBANE, III

A solution of 10 gm. of the optically active lactone of10,17u-dimethoxy-16fl-carboxy-l8B-hydroxy 318,201 yohimbane, II, wasprepared by introducing the lactone under nitrogen into the followingmixture:

Cc. Anhydrous methylene chloride 40 Anhydrous benzyl alcohol 12 Solutionof sodium benzylate containing 0.5% of sodium in benzyl alcohol 10 Vpropyl ether.

at reflux for a period of 16 hours. The reaction mixture was nextcooled, washed with Water until the wash waters were neutral, dried oversodium sulfate, filtered and the sodium sulfate washed several timeswith methylene chloride. Thefiltrate and the solvent of washing werecombined and brought to dryness under vacuum. The residue was taken upwith 50 cc. of isopropyl ether, vacuum filtered, triturated severaltimes with isopropyl ether and dried under vacuum. 11.5 gm. of rawlevorotatory 18fl-hydroxy-10,l7u' dimethoxy 16B carbobenzyloxy-3/3,20a-yohimbane, III, were obtained which was used as such for thenext step of the synthesis.

V The product was soiublein alcohol, acetone, benzene and'chloroform,and slightly soluble in ether and iso- STEP B.PRE'PARATION OF THELEVOROTATORY .HYDROCHLORIDE OF 18B-(3 ',4',5-TRIMETHOXYBEN- ZOYLOXY)10,17a DIMETHOXY-lfifl-CARBOBENZYL- OXY-3B,20a-YOHIMBANE, IV

11.5 gm. of raw levorotatory 18',8-hydroxy-10,17u-di-.

methoxy-16fi-carbobenzyloxy-3,8,20a-yohimbane, III, obtained accordingto the preceding step, and 19 gm. of 3,4,5-trimethoxybenzoic acidanhydride were introduced into a mixture of 35 cc. of anhydrous pyridineand 17 cc. of anhydrous tn'ethylamine. maintained under nitrogen for aperiod of 20 hours at 92 C.:*;l C.; then cc. of water were added and thesame conditions maintained for about 30 minutes more. Next, the reactionmixture was cooled and poured into 200' cc. "of water. i

The extraction of the reaction product, the free base, was effected in 4aliquotswi-th 50cc. of methylene chloride. The combined extracts werenext washed several times with water, then with a solution containing 2%ammonia, then again Withwater, then with an excess of 2 N hydrochloricacid and finally with water again. The extract was dried over sodiumsulfate, filtered and the sodium sulfate washed with methylene chloride.The filtrate and the solvent of washing Were combined and concentratedunder nitrogen to a reduced volume. 40 cc. of ethanol were added theretoand the distillation was continued under nitrogen until the start ofcrystallization. Then the mixture WHS COOIC dJaIld allowed to remainovernight in a refrigerator. The product was next vacuum filtered,triturated with iced ethanol, then with ether and dried under vacuum.7.3 gm. of the levorotatory hydrochloride gof1813-(3',4',5-trimethoxybenzoyloxy) 10,170; dimethoxy 16 3carbobenzyloxy- 3B,20u-yohimbane, IV, were obtained which product waspurified by repeatedrecrystallizations from a mixture of ethanol andmethylene chloride. The purified product had a melting point of 268270C. and a specific rotation .=65.2 (c.=1% in 1 part of ethanol and 2parts ofmethylene chloride). r

The product was soluble in the said mixture of ethanol and methylenechloride; very slightly soluble in alcohol, ether, acetone, benzene andchloroform; and insoluble in water. M r Analysis.C H O' N Cl:Calculated: 'C, 64.95%; H, 6.23 %;N, 3.88%; CI, 4.91%. Found: C, 64.9%;H, 6.5%; N, 3.9%; Cl, 5.0%.

This compound is not described in the literature.

STEP C.PREPARATION OF THE LEVOROTATORY HYDROCHLORIDE OF18B-(3',4,5TRIMETHOXYBEN- ZOYLOXY)-10,17a-DIMETHOXY-l6fl-CARBOXY35,2011- YOHIMBANE, V

A solution of 13.5 gm. of the levorotatary hydrochloride of18,8-(3',4,5'-trimethoxybenzoyloxy)-10,17u-dimethoxyd6fl-carbobenzyloxy-3fi,20a-yohimbane,IV, in 1,500 cc. of methanol was subjected to hydrogenolysis fora periodof 2 hours in the presence of 1.5 gm. of palladized carbon blackcontaining 10% palladium.

Next, the catalyst was separated by filtration and the filter cake waswashed with methanol. The filtrate and The reaction mixture was 525thesolvent of. washing were combined and concentrated to a reducedvolume. solution was next cooled for a period of 1 hour. The crystalsobtained were vacuum filtered, washed with iced methanol and dried undervacuum. a

9.5 gm. of the raw hydrochloride of 18B-'(3,4',5-trimethoxybenzoyl-oxy)10,170; dimethoxy 16B carboxy-3fi,20a-yohimbane, .V, were obtained,which product i and insoluble in water, alcohol, ether, acetone,benzene, V

chloroform, and dilute aqueous acids and alkalis.

Analysis.-C H O N Cl: Molecular weight=631.1. Calculated: C, 60.89%; H,6.23%;N, 4.43%; Cl, 5.62%. Found: C, 60.7%; H, 6.4%; N, 4.3%; Cl, 5.5.

This compound is not described in the literature. STEP D.PREPARATION OBLEVOROTATORY 18B-(3,4',

5'-TRIMETHOXYBENZOYLOXY)-10,17a DIMETHOXY-IGB-CARBOCAR.BOXYMETHOXY-3fi,20a YOHIMBANE,

I a I a 5 gm. of the hydrochloride of 18,8-(3,4,5-trimethoxybenzoyloxy)10,17a dimethoxy 16B carboxy 35, ZOu-yohimbane, V, were introduced into50 cc. of chloroform. 1.25 g. of anhydrous pyridine were added; then1.65 gm. of phosphorus pe-ntachloride were introduced and the reactionmixture was allowed to stand at rest for a period ot 16 hours at roomtemperature. Next, the reaction mixture was evaporated to dryness undervacuum. The residue was raw levorotatory 18[3-(-3',4,5'-trimethoxybenzoyloxy) 10,17cc dimethoxy 16,3carbochloride-3fl,20a-yohimbane, VI, and was used withoutfurther-purification in the next step of the synthesis.

This residue was taken up with 25 cc. of anhydrous chloroform. Asolution of 1.25. gm. of anhydrous 'glycolic acid in 10 cc. of anhydrouspyridine was added, and the reaction was allowed to occur during aperiod of 1 hour at room temperature. The reaction mixture was thenpoured into .a separatory funnel, washed with water, then with a diluteacetic acid solution and again with water. The reaction solution wasnext treated with animal black, filtered, and the filter cake washedwith chloroform. The wash liquid and solution were combined and broughtto dryness. The residue was taken tip with 25 cc. of water andtriturated, vacuum filtered, washed with water, then methanol and driedunder vacuum.

3.9 of raw levorot-atory 1'86-(3',4,5'trimethoxy oxy-3fi,20a-yohirnbane,I, were obtained which'was purified by solution in a mixture of ethanoland methylene chloride, filtration of the solution obtained anddistillation under nitrogen in order to remove the methylene chloride.The solution was iced for a period of 1 hour, vacuum filtered and 2 gm.of purified product (amorphous) were obtained, having a melting point of270- 275 C. and a specific rotation [a] =150.5i1 (c.=0.5% inchloroform).

The product occurred in the form of an amorphous powder, soluble inchloroform and dilute aqueous al- 'kalis; very slightly soluble inalcohol and acetone; and insoluble in water, ether, benzene and diluteaqueous acids.

Analysis.C H O N Molecular Calculated: C, 62.56%; H, 6.17%; N, 4.29%. C,62.3%; H, 6.4%; N, 4.2%.

This compound is not described in the literature.

The levorota-tory 181343,4',5-trimethoxybenzoyloxy)- wcight=652.7.Found:

l0,17a-dimethoXy-l6fl carbo-car-boxymethoxy 35,20 ayohimbane, I, soobtained can be neutralized with any therapeutically-acceptableinorganic or organic base to form a salt with the free car-boxy groupattached in the c.

16 position. Among such bases are the alkali metal hydroxides,carbonates, etc. primary aliphatic amines such as ethanolamine,methylamine, etc; and others.

4, The preceding specific embodiment of the invention is forillustrative purposes only and .is notto be'cons'trued as limiting theinvention. Such modifications and changes as would-be apparent to oneskilled in the art may be made Without. departing from the spirit of theinvention and the scope of the appended claims.

We claim: 7

1. A compound selected from the groupconsisting of nacemic and opticallyactive l3,8-(3,4,5'-trimethoxybenzoyloxy)-10,17oc dirnethoxy 16,8carbo-carboxymethoxy-3fl,20a-yohim-bane of the formula:

'and its alkali metal salts and its primary, aliphatic amine salts. i

2. Levorotatory 18,643,4',5-trimethoxybenzoyloxy)- 10,17d-dimethoxy46ficarbo carboXymethoxy-3p,20uyohimbane; v V

3. A process for the preparation of a compound se: lected from the groupconsisting of r-acemic and optically active 18B'-(3,4',5''trimethoxybenzoyloxy)-10,17a-dimethoXy-16fi-carbocarboxymethoxy-3fl-,mot-yohimbane of the formula:

OHBO

o Kiri/m no-fi-onhow 0 o 0- 0 CH3 and its alkali metal salts and itsprimary, aliphatic amine salts, which comprises the steps of esterifyingthe 16,18 lactone of 18,8-hydrox-y-10,l7a-dirnethoxy-l6fi-carboxy-35,20u-yohimbane with benzyl alcohol in the presence of an alkali metalbenzylate, subjecting the 18fi-hydroxy- 10,17 -dimethoxy16/3-carbobenzyloXy 3fi,20a-yohimo a o V bane obtained to the action ofan esteri-fying derivative of 3,4,5-trime-thoxy benzoic acid selectedfrom the group consisting of the acid anhydride and the acid chloride inthe presence of an organic nitrogen solvent, subjecting the 1 8 ,6-3,4',5 '-tr=imetho:ZybenzoyloXy) -10, 17a-dimethoxy-l6fl-carbobenzyloxy;3fi,20u-yohimbane obtained to hydrogenolysisin the presence of a hydrogenolysis catalyst, reacting the18B-(3,4,5'-trmethoxybenzoyloxy)- tained with phosphorus pentachloridein an inert organic solvent, esterifying the18Q-(3',4',5'trimethoxybenzoyloxy)- 1Q,17a dimethoxy-16,8-carbochloride35,20a-yohimbane obtained with glycolic acid in the presence of anorganic nitrogen solvent and recovering said 18,8

(3,4',5'-trimethoxybcnzoyloxy)-l0,l7udimethoXy-16flcarbo-carboXymethoXy-3,BJOa-yohimbane compounds.

4. A process for the preparation of a compound selected from the groupconsisting of racemic and optically active1SB-(3,4',5-trimethoxybenzoyloxy) 10,17oc dimethoxy-16B-canbocar'boxymethoxy-3B-,20u-yohimbane of the formula:

O CH:

References Cited in the fileof this patent UNITED STATES PATENTS KuehneOct. 2 1, 1958 3,031,453 Lucas Apr. 24, 1962 FOREIGN PATENTS 1,029,003Germany Apr. 30, 1958 OTHER REFERENCES V Wagner et al.:-Synthetic OrgChem, Wiley and Sons, New York (1953), pages 480, 482.

Groggins: Unit Processes in Org.- Synthesis, McGraw- Hill, New York(1958'), pages 717and 718.

2. LEVOROTATORY 18B-(3'',4'',5''-TRIMETHOXYBENZOYLOXY),10,17A-DIMETHOXY-16B - CARBO - CARBOXYMETHOXY-OB,20AYOHIMBANE.